The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure.

Claudia Galassi,Nicoletta Manduca,Martina Musella,Antonella Sistigu,Ester Maccafeo

doi:10.3390/cells10092361

Abstract

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs.

Highlights

Cancer is an evolving and dynamic disease whose progression may result in intratumoral heterogeneity (ITH) that confers different levels of sensitivity, and fuels resistance to conventional, targeted and immune-based therapies [1]
The identification and isolation of cancer stem cells (CSCs) is mainly based on the expression of surface proteins shared with normal stem cells (such as human embryonic stem cells), including the antigens CD34, CD38, prominin 1 (PROM1; best known as CD133), CD44, its variant isoform CD44v6, CD24, activated leukocyte cell adhesion molecule (ALCAM; best known as CD166), epithelial cell adhesion molecule (EPCAM), leucine rich repeat containing G protein-coupled receptor 5 (LGR5), ephrin receptors and the activity of the aldehyde dehydrogenases (ALDHs) [7,8] (Table 1)
A flurry of studies in the field of “2D onco-immunology”, revealed the molecular pathways and effectors involved in the crosstalk between cancer cells with stem-like properties and different subsets of immune cells, including tumor associated macrophages (TAMs), dendritic cells (DCs), T regulatory cells (Tregs), αβ and γδ T cells [117]

Summary

Introduction

Cancer is an evolving and dynamic disease whose progression may result in intratumoral heterogeneity (ITH) that confers different levels of sensitivity, and fuels resistance to conventional, targeted and immune-based therapies [1]. The identification and isolation of CSCs is mainly based on the expression of surface proteins shared with normal stem cells (such as human embryonic stem cells (hESCs)), including the antigens CD34, CD38, prominin 1 (PROM1; best known as CD133), CD44, its variant isoform CD44v6, CD24, activated leukocyte cell adhesion molecule (ALCAM; best known as CD166), epithelial cell adhesion molecule (EPCAM), leucine rich repeat containing G protein-coupled receptor 5 (LGR5), ephrin receptors and the activity of the aldehyde dehydrogenases (ALDHs) [7,8] (Table 1) Despite these findings, a universal, highly sensitive and specific marker for CSCs is still lacking [8,9]. CSCs are endowed with the ability to repair DNA damage through a robust DNA damage response (DDR) machinery [13] and to withstand high levels of replication stress by flaunting replication stress responses (RSRs) [14] Another factor conferring therapeutic resistance to CSCs is the ability to enter dormancy [15] and acquire an anti-apoptotic state [16]. CSC (re)fueling and cancer elimination, while therapies exclusively based on intrinsic CSC features represent a short-term and temporary cancer (stem) cell eradication without the achievement of a long-lasting disease-free survival

The Immune Privileged Status of CSCs

Immunomodulatory Traits of CSCs and Their Immune Context

Immunotherapeutic Strategies against CSCs

Concluding Remarks